Mechanobiological insight into brain diseases based on mechanosensitive channels: Common mechanisms and clinical potential.

BACKGROUND: As physical signals, mechanical cues regulate the neural cells in the brain. The mechanosensitive channels (MSCs) perceive the mechanical cues and transduce them by permeating specific ions or molecules across the plasma membrane, and finally trigger a series of intracellular bioelectrical and biochemical signals. Emerging evidence supports that wide-distributed, high-expressed MSCs like Piezo1 play important roles in several neurophysiological processes and neurological disorders. AIMS: To systematically conclude the functions of MSCs in the brain and provide a novel mechanobiological perspective for brain diseases. METHOD: We summarized the mechanical cues and MSCs detected in the brain and the research progress on the functional roles of MSCs in physiological conditions. We then concluded the pathological activation and downstream pathways triggered by MSCs in two categories of brain diseases, neurodegenerative diseases and place-occupying damages. Finally, we outlined the methods for manipulating MSCs and discussed their medical potential with some crucial outstanding issues. RESULTS: The MSCs present underlying common mechanisms in different brain diseases by acting as the "transportation hubs" to transduce the distinct signal patterns: the upstream mechanical cues and the downstream intracellular pathways. Manipulating the MSCs is feasible to alter the complicated downstream processes, providing them promising targets for clinical treatment. CONCLUSIONS: Recent research on MSCs provides a novel insight into brain diseases. The common mechanisms mediated by MSCs inspire a wide range of therapeutic potentials targeted on MSCs in different brain diseases.

Progress of Mitochondrial Function Regulation in Cardiac Regeneration.

Heart failure and myocardial infarction, global health concerns, stem from limited cardiac regeneration post-injury. Myocardial infarction, typically caused by coronary artery blockage, leads to cardiac muscle cell damage, progressing to heart failure. Addressing the adult heart's minimal self-repair capability is crucial, highlighting cardiac regeneration research's importance. Studies reveal a metabolic shift from anaerobic glycolysis to oxidative phosphorylation in neonates as a key factor in impaired cardiac regeneration, with mitochondria being central. The heart's high energy demands rely on a robust mitochondrial network, essential for cellular energy, cardiac health, and regenerative capacity. Mitochondria's influence extends to redox balance regulation, signaling molecule interactions, and apoptosis. Changes in mitochondrial morphology and quantity also impact cardiac cell regeneration. This article reviews mitochondria's multifaceted role in cardiac regeneration, particularly in myocardial infarction and heart failure models. Understanding mitochondrial function in cardiac regeneration aims to enhance myocardial infarction and heart failure treatment methods and insights.

Stress can affect mitochondrial energy metabolism and AMPK/SIRT1 signaling pathway in rats.

OBJECTION: To investigate the potential link between aberrant mitochondrial energy metabolism mediated by the AMPK/SIRT1 pathway and the etiology of anxiety disorders. METHODS: The anxiety rat model was established by uncertain empty water bottle（UEWB）stress. Rats were submitted behavioral tests on the seventh, fourteenth, and twenty-first days and had the prefrontal cortex and amygdala removed for biochemical tests. The morphological alterations of the mitochondria in the medial prefrontal cortex and amygdala were examined by using a transmission electron microscope. Expression levels of AMPK, SIRT1, PGC-1, NRF-1 and NRF-2 were tested by western-blot analysis. ATP, respiratory chain complex and caspase enzyme expressions were tested by neurochemical and biochemical assays. RESULTS: Rats showed anxiety-like behavior after being exposed to the uncertain empty water bottle (UEWB) stress model. In model rats, mitochondrial structure is damaged, mitochondrial energy metabolism is decreased, and the expression of proteins associated with AMPK/SIRT1 pathway is significantly reduced in the brain. CONCLUSION: The level of mitochondrial energy metabolism correlates with anxiety-like behavior. The main mechanism of anxiety disorder is a disturbance of mitochondrial energy metabolism, which might be related to AMPK/SIRT1 pathway.

TRIM69: a marker of metastasis and potential sensitizer to 5-Fluorouracil and PD-1 blockers in colon adenocarcinoma.

BACKGROUND: Several proteins in the tripartite-motif (TRIM) family are associated with the development of colorectal cancer (CRC), but research on the role of TRIM69 was lacking. The present study examined the correlation between TRIM69 expression and colon adenocarcinoma (COAD). METHODS: mRNA sequencing data for COAD patients was extracted from The Cancer Genome Atlas to analyze correlations between TRIM69 expression and patients' clinical features as well as survival. Potential associations with immune cells and chemosensitivity also were predicted using various algorithms in the TIMER, Limma, clusterProfiler, GeneMANIA, and Gene Set Cancer Analysis platforms. Subsequently, polymerase chain reaction analysis and immunohistochemical staining were used to detect TRIM69 expression in COAD tissue samples from real-world patients. RESULTS: TRIM69 expression was lower in COAD tissues than in normal tissues and correlated with the pathologic stage and metastasis (M category). Additionally, TRIM69 was found to be involved in several immune-related pathways, notably the NOD-like signaling pathway. These results suggest that high TRIM69 expression has the potential to enhance tumor sensitivity to 5-fluorouracil and programmed cell death protein 1 (PD-1) blockers. CONCLUSIONS: From our findings that TRIM69 expression was significantly reduced in COAD compared with non-cancer tissues and associated with pathologic stage and metastasis, we conclude that increasing TRIM69 expression and/or activity may help to improve therapeutic outcomes. Accordingly, TRIM69 represents a potentially valuable marker of metastasis and target for adjuvant therapy in COAD.

[Effect of Danzhi Xiaoyao Powder on behavior and mitochondrial morphology and function of anxiety model rats].

Danzhi Xiaoyao Powder is a classical prescription for anxiety. This study aims to analyze the effect of this medicine on mitochondrial morphology and function of anxiety rats and explore the mechanism of it against anxiety. Specifically, uncertain empty bottle drinking water stimulation(21 days) was employed to induce anxiety in rats. The elevated plus-maze test and open field test were respectively performed on the 7 th, the 14 th, and the 21 st days of the stimulation, so as to detect the anxiety-related protein index brain-derived neurotrophic factor(BDNF) and evaluate the anxiety level of animals. On this basis, the effect of this prescription on anxiety rats was preliminarily evaluated. After the behavioral test on the 21 st day, rats were killed and the brain tissues were separated for the observation of the mitochondrial morphology and the determination of mitochondrial function-related indicators and the adenosine 5'-monophosphate-activated protein kinase(AMPK) level. The results showed that Danzhi Xiaoxiao Powder could alleviate the anxiety-like behavior of rats, significantly increase the percentage of time in open arm in elevated plus-maze test and the ration of activity time in the central area of the field, dose-dependently raise the activity levels of respiratory chain complex Ⅰ,Ⅱ,Ⅲ and Ⅳ and the adenosine triphosphate(ATP) content, and elevate the levels of BDNF and phosphorylated AMPK(p-AMPK). Clear structure and intact morphology of mitochondrial cristae in medial prefrontal cortex cells and amygdala were observed in the Danzhi Xiaoyao Powder group. In summary, Danzhi Xiaoyao Powder exerts therapeutic effect on anxiety, and the mechanism is the likelihood that p-AMPK protects the structure and maintains the function of mitochondria.